Therapeutic compositions for intranasal administration which include ketorolac

ABSTRACT

An analgesic/anti-inflammatory pharmaceutical dosage form which comprises an effective amount of an active ingredient selected from the group consisting of racemic 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, optically active forms thereof and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient or diluent, said dosage form being an intranasally administrable dosage form.

FIELD OF THE INVENTION

[0001] This invention relates to therapeutic compositions with analgesicand anti-inflammatory activity, suitable for intranasal administration,which include KETOROLAC® or its pharmaceutically acceptable salts as theactive ingredient.

[0002] This invention also relates to a therapeutic method whichprovides for the administration of KETOROLAC® or its salts by theintranasal route.

BACKGROUND OF THE INVENTION

[0003] KETOROLAC® or 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylicacid, the formula of which is:

[0004] has been known for several years (U.S. Pat. No. 4,089,969) and isused in human therapy as an analgesic and an anti-inflammatory.

[0005] Both the racemic form and each of the dextro and levo isomers ofthis compound are known. Many pharmaceutically acceptable salts, themost commonly used of which is the tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol) salt, are also known.Hereinafter, the name KETOROLAC® shall encompass individually orcollectively the racemic mixture or either optically active compound andshall encompass the free acid as well as the tromethamine salt or anyother pharmaceutically acceptable salt of any one of the foregoing.

[0006] Ample literature is available on KETOROLAC® (for instance,“KETOROLAC®—A review of its pharmacodynamic and pharmacokineticproperties and its therapeutic potential”, Drugs 39(1): 86-109, 1990. Itis described as a drug with considerably higher analgesic andanti-inflammatory activity than many other non-steroid anti-inflammatorydrugs. Most significantly, it has higher analgesic activity thanmorphine, without the well-known side effects of the latter.

[0007] In the several pharmacological and clinical trials involvingKETOROLAC® that have been conducted, this drug was administered both bythe oral route and by injection (in turn, both intravenous andintramuscular). Regardless of the administration route, KETOROLAC®proved active and was found comparatively more active than the betterknown non-steroid drugs with analgesic and anti-inflammatory activity.However, about 10% of the patients treated (20 doses of 30 mg eachadministered over five days) by the intramuscular route suffered fromone or more undesirable side effects such as somnolence, local(injection site) pain, sweating, nausea, headache, dizziness, vomiting,pruritus, and vasodilation.

[0008] The incidence of side effects was even higher (around 32%) in thepatients treated with KETOROLAC® by the oral route for a few days. Inthe case of oral administration, gastrointestinal disorders (nausea,g.i. pain, dyspepsia, diarrhea, flatulence, g.i. fullness, vomiting)were noted in up to 50% of the patients in addition to side effectsincident to i.m. administration.

[0009] Intravenous administration is inconvenient and is limited to thetreatment of acute conditions.

[0010] On the whole, the data available to date clearly describe a drugwhich is very active, but still unsatisfactory from the point of view ofconvenience of administration and/or side effects.

SUMMARY OF THE INVENTION

[0011] We have now found that it is possible to prepareanalgesic/anti-inflammatory formulations containing KETOROLAC® as anactive ingredient, which are suitable for intranasal administration andthat KETOROLAC® so administered is rapidly and thoroughly absorbed,giving therapeutic effects equivalent to those obtained by theintravenous route (acute treatments) or the intramuscular or oral routes(extended or chronic treatments), without inducing severe side effects.Most important, any possibility of gastrointestinal disorders isexcluded, while disorders caused by CNS stimulation are considerablyreduced both in incidence (e.g. number of patients affected) andintensity.

[0012] Another aspect of the present invention is directed to atherapeutic method for the treatment of inflammatory processes and forthe therapy of pain of a traumatic or pathologic origin, which methodcomprises administering by the intranasal route ananalgesic/anti-inflammatory amount of KETOROLAC® along with anabsorption promoter and pharmaceutically acceptable diluents and/orexcipients.

[0013] The new method provides for the intranasal administration ofKETOROLAC® doses ranging between 0.5 and 40 mg, preferably between 5 and30 mg, and is particularly effective in acute therapies, where a veryrapid systemic delivery is required especially one not accompanied bythe drawbacks of i.v. delivery (hospitalization, cost, etc.).

DETAILED DESCRIPTION OF THE INVENTION

[0014] All cited patents and literature are incorporated by reference intheir entirety.

[0015] Although nasal administration to mammals (especially humans) ofcertain therapeutic agents is known, it is not to be presumed that alltherapeutic agents can be effectively administered by this route. To thecontrary, many therapeutic agents cannot be nasally administered. Atpresent, the molecules which have proved suitable for this route ofadministration are still very few and consist essentially of only smallpeptide or hormone molecules (such as calcitonin, cerulean, β-endorphin,glucagon, horseradish peroxidase, B-interferon, oxytocin and insulin) inspecial formulations. The ability of drug molecules to be absorbed bythe nasal mucous membranes is utterly unpredictable, as is the abilityof intranasal formulations to avoid irritation of the mucous nasalmembranes. In fact, mucous membrane irritation caused by the drug and/orexcipient is the most common reason for which intranasal administrationhas not gained wider acceptance.

[0016] The new compositions according to the invention include theactive ingredient in quantities ranging from 0.5 to 40 mg per dose,preferably 5 to 30 mg per dose, diluted in excipients such ashumectants, isotoning agents, antioxidants, buffers and preservatives. Acalcium chelating agent is also preferably included.

[0017] The intranasal formulations of the invention contain KETOROLAC®concentrations ranging from 5 to 20%, preferably about 15%weight/volume. Of course, the selection of the particular excipientsdepends on the desired formulation dosage form, i.e. on whether asolution to be used in drops or as a spray (aerosol) is desired or asuspension, ointment or gel to be applied in the nasal cavity aredesired. In any case, the invention make it possible to have single-dosedosage forms, which ensure application of an optimum quantity of drug.

[0018] Administration of the present intranasal formulations providesvery good absolute bioavailability of KETOROLAC, as demonstrated intests involving rabbits. The predictive value of the rabbit model withrespect to bioavailability of nasally administered KETOROLAC® in humansis art-recognized (Mroszczak, E. J. et al., Drug Metab. Dispos.,15:618-626, 1987, especially Tables 1 and 3). According to the resultsof the rabbit tests set forth below it is extrapolated that in humansintranasal administration of a composition according to the invention inamounts ranging between 0.5 mg/kg/day and 4 mg/kg/day will generateplasma levels of KETOROLAC® within the range of 0.3-5 mg/liter ofplasma.

[0019] Suitable vehicles for the formulations according to the inventioninclude aqueous solutions containing an appropriate isotoning agentselected among those commonly used in pharmaceutics. Substances used forthis purpose are, for instance, sodium chloride and glucose. Thequantity of isotoning agent should impart to the vehicle (taking intoaccount the osmotic effect of the active ingredient), an osmoticpressure similar to that of biological fluids, i.e. generally from about150 to about 850 milliOsmoles (mOsm) preferably from about 270 to about330 mOsm.

[0020] However, it is known that nasal mucous membranes are also capableof tolerating slightly hypertonic solutions. Should a suspension or gelbe desired instead of a solution, appropriate oily or gel vehicles maybe used or one or more polymeric materials may be included, whichdesirably should be capable of conferring bioadhesive characteristics tothe vehicle.

[0021] Several polymers are used in pharmaceutics for the preparation ofa gel; the following can be mentioned as nonlimiting examples:hydroxypropyl cellulose (KLUCEL®), hydroxypropyl methyl cellulose(METHOCEL®), hydroxyethyl cellulose (NATROSOL®), sodium carboxymethylcellulose (BLANOSE®), acrylic polymers (CARBOPOL®, POLYCARBOPHIL®), gumxanthan, gum tragacanth, alginates and agar-agar.

[0022] Some of them, such as sodium carboxymethyl cellulose and acrylicpolymers, have marked bioadhesive properties and are preferred ifbioadhesiveness is desired.

[0023] Other formulations suitable for intranasal administration ofKETOROLAC® can be obtained by adding to the aqueous vehicle polymerscapable of changing the rheologic behavior of the composition inrelation to the temperature. These polymers make it possible to obtainlow viscosity solutions at room temperature, which can be applied forinstance by nasal spray and which increase in viscosity at bodytemperature, yielding a viscous fluid which ensures a better and longercontact with the nasal mucous membrane. Polymers of this class includewithout limitation polyoxyethylene-polyoxypropylene block copolymers(POLOXAMER®).

[0024] In addition to aqueous, oil or gel vehicles, other vehicles whichmay be used in the compositions according to the invention comprisesolvent systems containing ethyl alcohol, isopropyl alcohol, propyleneglycol, polyethylene glycol, mixtures thereof or mixtures of one or moreof the foregoing with water.

[0025] In any case, a pharmaceutically acceptable buffer should bepresent in order to create optimum pH conditions for both productstability and tolerance (pH range about 4 to about 8; preferably about5.5 to 7.5). Suitable buffers include without limitation tris(tromethamine) buffer, phosphate buffer, etc.

[0026] Other excipients include chemical enhancers such as absorptionpromoters. These include chelating agents, fatty acids, bile acid saltsand other surfactants, fusidic acid, lysophosphatides, cyclic peptideantibiotics, preservatives, carboxylic acids (ascorbic acid, aminoacids), glycyrrhetinic acid, o-acylcarnitine. Preferred promoters arediisopropyladipate, POE(9) lauryl alcohol, sodium glycocholate andlysophosphatidyl-choline which proved to be particularly active.Finally, the new compositions according to the invention preferablycontain preservatives which ensure the microbiological stability of theactive ingredient. Suitable preservatives include without limitation,methyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate, benzylalcohol, benzalkonium chloride and chlorobutanol.

[0027] The liquid KETOROLAC® formulations, preferably in the form ofsolutions, may be administered in the form of drops or spray, usingatomizers equipped with a mechanical valve and possibly including apropellant of a type commercially available, such as butane, N₂, Ar,C02, nitrous oxide, propane, dimethyl ether, chlorofluorocarbons (e.g.FREON) etc. Vehicles suitable for spray administration are water,alcohol, glycol and propylene glycol, used alone or in a mixture of twoor more.

[0028] Generally, illustrative formulations will contain the followingingredients and amounts (weight/volume): Ingredient Broad Range (%)Preferred Range (%) Na₂ EDTA 0.001-1   0.05-0.1 Nipagin 0.01-2  0.05-0.25 POE(9) Lauryl alcohol  0.1-10   1-10 NaCMC (Blanose 7m8 sfd) 0.1-5 0.3-3 Carbopol 940 0.05-2   0.1-1.5 Glycerol    1-99 Sodiumglycocholate 0.05-5 0.1-1

[0029] It will be appreciated by those of ordinary skill thatingredients such as sodium carboxymethyl cellulose and Carbopol exist inmany types differing in viscosity. Their amounts are to be adjustedaccordingly. Different adjustments to each formulation may also benecessary including omission of some optional ingredients and additionof others. It is thus not possible to give an all-encompassing amountrange for each ingredient, but the optimization of each preparationaccording to the invention is within the skill of the art.

[0030] Another, although not preferred, alternative for the intranasaladministration of the KETOROLAC®-based compositions comprises asuspension of finely micronized active ingredient (generally from 1 to200 micrometers, preferably from 5 to 100 micrometers) in a propellantor in an oily vehicle or in another vehicle in which the drug is notsoluble. The vehicle is mixed or emulsified with the propellant.Vehicles suitable for this alternative are, for instance, vegetable andmineral oils and triglyceride mixtures. Appropriate surfactants,suspending agents and diluents suitable for use in pharmaceutics areadded to these vehicles. Surfactants include without limitation sorbitansesquioleate, sorbitan monooleate, sorbitan trioleate (amount: betweenabout 0.25 and about 1%); suspending agents include without limitationisopropylmyristate (amount: between about 0.5 and about 1%) andcolloidal silica (amount: between about 0.1 and about 0.5%); anddiluents include without limitation zinc stearate (about 0.6 to about1%).

[0031] The following examples of formulations for the intranasaladministration of KETOROLAC® serve to illustrate the invention withoutlimiting its scope.

EXAMPLE 1

[0032] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 g EDTAdisodium (chelating agent) 0.01 1 g NIPAGIN (preservative) 0.1 10 gPurified water, q.s. to 100 10 L

[0033] Method of Preparation

[0034] In a suitable vessel equipped with mixer and heating sleeve,introduce about 9 liters of purified water and heat to a temperature of80° C.

[0035] Dissolve NIPAGIN and EDTA disodium.

[0036] Stir the solution constantly to complete dissolution of thecomponents.

[0037] Cool the obtained solution to room temperature.

[0038] Dissolve KETOROLAC® tromethamine by stirring.

[0039] Bring to volume with water.

[0040] The isotonicity of this composition was 190 mOsm but can beadjusted e.g. to 270 mOsm by the addition of 0.3% NaCl or 2.03% ofglucose.

EXAMPLE 2

[0041] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 g POE(9) lauryl alcohol (enhancer/promoter) 5 500 g NIPAGIN 0.1 10 g EDTAdisodium 0.01 1 g Purified water, q.s. to 100 10 L

[0042] Method of Preparation

[0043] In a suitable vessel equipped with mixer and heating sleeve,introduce about 9 liters of purified water and heat to a temperature of80° C.

[0044] Dissolve NIPAGIN and EDTA disodium.

[0045] Stir the solution constantly to complete dissolution of thecomponents.

[0046] Cool the obtained solution to room temperature.

[0047] Add POE (9) lauryl alcohol and stir to complete dissolution.

[0048] Dissolve KETOROLAC® tromethamine by stirring.

[0049] Bring to volume with water.

EXAMPLE 3

[0050] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 gSodium carboxymethyl cellulose 1 100 g Tromethamine, q.s. to pH = 6NIPAGIN 0.1 10 g Purified water, q.s. to 100 10 L

[0051] Method of Preparation

[0052] In a suitable vessel equipped with mixer and heating sleeve,introduce about 9 liters purified water and heat to a temperature of 80°C.

[0053] Dissolve NIPAGIN.

[0054] Cool the obtained solution to room temperature.

[0055] Dissolve KETOROLAC® and continue stirring to complete dissolutionof the drug.

[0056] Disperse sodium carboxymethyl cellulose in the solution stirringvigorously.

[0057] Continue stirring to complete hydration of the polymer.

[0058] Adjust the pH to the required value by suitably addingtromethamine dissolved in water.

[0059] Bring to volume with water.

EXAMPLE 4

[0060] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 gNIPAGIN 0.1 10 g EDTA disodium 0.01 1 g CARBOPOL 940 0.1 10 gTromethamine, q.s. to pH = 7-7.4 Glycerol 2 200 g Purified water, q.s.to 100 10 L

[0061] Method of Preparation

[0062] In a suitable vessel equipped with mixer and heating sleeve,introduce about 4 liters of purified water and heat to a temperature of80° C.

[0063] Dissolve NIPAGIN and EDTA.

[0064] Cool the solution to room temperature.

[0065] Dissolve KETOROLAC® tromethamine.

[0066] Complete the dissolution of the active ingredient and adjust thepH to a value of 7.1-7.4 by adding a 5% tromethamine solution.

[0067] In a separate vessel equipped with mixer, introduce the quantityof glycerol called for in the formulation.

[0068] Introduce CARBOPOL and mix until a homogeneous dispersion in theglycerol is obtained.

[0069] Add 4 liters of purified water with vigorous stirring andcontinue stirring the solution to complete hydration of the polymer.

[0070] Combine the solution containing the active ingredient and thepolymer solution with stirring.

[0071] If necessary, adjust the pH to the required value with thetromethamine solution.

[0072] Bring to volume with water.

EXAMPLE 5

[0073] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 gLUTROL F127 17 1.7 Kg EDTA disodium 0.01 1 g NIPAGIN 0.1 10 g Purifiedwater, q.s. to 100 10 L

[0074] Method of Preparation

[0075] In a suitable vessel equipped with mixer and heating sleeve,introduce about 4 liters of purified water and heat to a temperature of80° C.

[0076] Dissolve NIPAGIN and EDTA disodium.

[0077] Cool the solution to 4° C. and then, maintaining it between 4 and6° C. throughout the operation, gradually add Lutrol F127 with stirring.

[0078] Continue stirring to complete hydration of the polymer.

[0079] Bring the solution to room temperature.

[0080] Dissolve KETOROLAC® tromethamine.

[0081] Bring to volume with water.

EXAMPLE 6

[0082] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 gSodium carboxymethyl cellulose 2 200 g EDTA disodium 0.01 1 g NIPAGIN0.1 10 g Purified water, q.s. to 100 10 L

[0083] The procedure of Example 3 was used to make the above formulationexcept that no buffer was added.

EXAMPLE 7

[0084] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 gLUTROL F127 15 1500 g EDTA disodium 0.01 1 g NIPAGIN 0.1 10 g PurifiedWater, q.s. to 100 10 L

[0085] The procedure of Example 5 was used to make the aboveformulation.

EXAMPLE 8

[0086] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 g EDTAdisodium 0.01 1 g NIPAGIN 0.1 10 g Sodium glycocholate 0.3 30 g Purifiedwater, q.s. to 100 10 L

[0087] The procedure of Example 1 was used except that sodiumglycocholate was dissolved with the nipagin and disodium EDTA at 80° C.in water. The isotonicity of this composition was 190 mOsm; it can beadjusted e.g. to 330 mOsm by the addition of 0.44% NaCl or 3.05%glucose.

EXAMPLE 9

[0088] Composition % For 10 liters KETOROLAC ® tromethamine 5 500 gLutrol F127 15 1500 g Sodium glycocholate 0.3 30 g EDTA disodium 0.01 1g NIPAGIN 0.1 10 g Purified water, q.s. to 100 10 L

[0089] The procedure of Example 5 was used except that sodiumglycocholate was dissolved along with nipagin and disodium EDTA at 80°C.

EXAMPLE 10

[0090] We studied the stability of the preparations described in theExamples 1, 2, 6, 7, 8 and 9. The storing conditions were 4° C., 22° C.,45° C. and 55° C. We analyzed the preparations at the beginning of thestoring period and after 1, 2, 3 and 6 months. We used UV and HPLCanalysis.

[0091] The parameters tested were:

[0092] content of active compound (UV and HPLC)

[0093] content of keto and hydroxy degradation products (UV and HPLC)

[0094] appearance and color (visual examination)

[0095] pH (digital pH meter)

[0096] The results are summarized in Table 1. TABLE 1 Ex- am- Temp. KTMKeto Hydroxy Appearance ple ° C. Months (mg/ml) % % of solution pH 1 220 50.1 0.8 0.3 light yellow 6.2 45 2 50.8 0.2 0.0 yellow 6.5 45 3 49.60.2 0.0 opalescent 6.5 yellow 45 6 51.4 0.4 0.0 yellow with 6.5 deposit2 22 0 49.0 0.1 0.3 light yellow 6.4 45 2 47.7 0.4 0.0 yellow 6.8 45 346.7 0.2 0.0 yellow 6.9 45 6 47.3 1.0 0.0 yellow 7.0 6 22 0 49.6 0.1 0.4yellow 6.0 45 1 47.0 0.1 0.1 yellow 6.5 45 3 48.8 0.2 0.0 yellow 6.5 456 50.1 0.9 0.0 yellow with 5.5 deposit 7 22 0 48.5 0.0 0.5 light yellow6.7 55 1 49.0 0.8 0.0 yellow gel 6.8 55 3 47.1 1.4 1.9 orange gel 6.6 822 0 52.3 0.0 0.0 light yellow 6.2 45 1 53.2 0.0 0.0 yellow 6.4 45 354.3 0.5 0.0 yellow 6.5 9 22 0 48.7 0.0 0.0 light yellow 6.7 45 1 51.70.0 0.0 yellow 6.8

EXAMPLE 11

[0097] We tested in vitro the thermosetting properties of somepreparations (Examples 1, 2, 7, 9). We sprayed a standardized amount ofevery preparation to a 37° C. constant-temperature, vertical glasssurface and we measured the time that the drops of preparation spent tocover 10 cm. The speed of solution in moving on the constant-temperaturesurface is an indicator of the thermosetting properties of the dosageform. Examples 7 and 9 gave the best results in terms of thermosettingproperties.

[0098] The results are reported in Table 2. TABLE 2 Preparation Time toCover 10 cm H₂O 3 sec. Example 1 3 sec. Example 2 3 sec. Example 7 12sec. Example 9 15 sec.

EXAMPLE 12

[0099] We studied the nasal absorption and the local tolerance of fourpreparations (Examples 1, 6, 8, 9) in White New Zealand rabbits (threerabbits for each experimental group plus three controls). Each rabbitreceived a active preparation in one nostril and its placebo in theother. Each animal received 2 mg/kg of KETOROLAC® tromethamine (KTM),twice a day for seven days and once on the eighth day. The controlrabbits were treated, after seven days of nasal administration ofphysiologic solution, with 2 mg/kg of KTM by intravenous route once.After the last treatment plasma samples were collected at several timesand KTM plasma levels were investigated by HPLC. After the last bloodsample was drawn all the animals were killed by excision of femoralarteries, after having been completely anaesthetized. Nasal turbinates,larynx and pharynx were removed and subjected to histologicalexaminations.

[0100] Pharmacokinetic parameters are reported in Tables 3, 4, 5, 6, 7and in FIG. 1. The local (nasal mucous) tolerance data showed goodtolerance of the KETOROLAC-containing intranasal preparations with theformulation of Example 1 being the best tolerated followed by that ofExample 6, Example 9 and Example 8 in that order. TABLE 3 ControlAbsorption of KTM Route of Administration: Intravenous AdministeredDose: 2 mg/kg Plasma Concentration of KTM as ng/ml Sampling Time (hours)Mean ± S.D. Basal   0  0 0.083 14510  1999  0.25 7682 2887  0.5 38841891  1 1703 792 2  403 167 3  120  67 5  20  7

[0101] TABLE 4 Nasal Absorption of KTM Composition: Example 1 Route ofAdministration: Intranasal Administered Dose: 2 mg/kg/administrationSampling Time (hours) Mean ± S.D. Basal  18  16 0.25 2363  1035  0.51875  726 1 1103  490 2 593 217 3 267  55 5 121  52

[0102] TABLE 5 Nasal Absorption of KTM Composition: Example 8 Route ofAdministration: Intranasal Administered Dose: 2 mg/kg/administrationSampling Time (hours) Mean ± S.D. Basal  29  22 0.25 2973 1258  0.5 2654880 1 2246 1145  2 1121 832 3  665 444 5  427 194

[0103] TABLE 6 Nasal Absorption of KTM Composition: Example 9 Route ofAdministration: Intranasal Administered Dose: 2 mg/kg/administrationSampling Time (hours) Mean ± S.D. Basal  35  17 0.25 2036  572 0.5 1663 778 1 1009  345 2 325 103 3 184  22 5 198  52

[0104] TABLE 7 Nasal Absorption of KTM Composition: Example 6 Route ofAdministration: Intranasal Dose Administered: 2 mg/kg/administrationSampling Time (hours) Mean ± S.D. Basal  23  20 0.25 1872  1228  0.51772  1027  1 1213  619 2 616 293 3 269  96 5 133  23

[0105] From the foregoing data, the following bioavailability parameterswere calculated: TABLE 8 Example 1 Example 8 Example 9 Example 6Formulation i.v. (A) (B) (C) (D) AUC₀₋₅ (h.ng/ml) average 7355 3237 59722692 3197 ± S.D. 2405 1129 2973 571 976 CV (%) 32.7 34.9 49.8 21.2 30.5T_(max) (hours) average 0.25 0.42 0.33 0.33 ± S.D. 0 0.14 0.14 0.14 CV(%) 0 34.6 43.3 43.3 C_(max) (ng/ml) average 2363 3226 2229 1895 ± S.D.1035 1079 335 1203 CV (%) 43.8 33.4 15.0 63.5 AUC i.n./AUC i.v. average0.44 0.81 0.36 0.43

[0106] The foregoing results indicate that intranasal formulations ofKETOROLAC® according to the invention compare favorably with intravenousformulations in terms of absorption (Formulation B from Example 8 beingthe best absorbed), time to maximum plasma concentration, and maximumplasma concentration and exhibit good absolute bioavailability(especially formulation B).

EXAMPLE 13

[0107] Composition % For 10 Liters KETOROLAC ® tromethamine 15 1500 gEDTA disodium 0.01 1 g NIPAGIN 0.2 20 g Purified water, q.s. to 100 10 L

[0108] Method of Preparation

[0109] In a suitable vessel equipped with mixer and heating sleeve,introduce about 9 liters of purified water and heat to a temperature of80° C.

[0110] Dissolve NIPAGIN and EDTA disodium

[0111] Stir the solution constantly to complete dissolution of thecomponents.

[0112] Cool the obtained solution to room temperature.

[0113] Dissolve KETOROLAC® tromethamine by stirring.

[0114] Bring to volume with water.

EXAMPLE 14

[0115] Composition % For 10 Liters KETOROLAC ® tromethamine 15 1500 gEDTA disodium 0.01 1 g NIPAGIN 0.2 20 g Glycocholic acid 0.3 30 gPurified water, q.s. to 100 10 L

[0116] Method of Preparation

[0117] In a suitable vessel equipped with mixer and heating sleeve,introduce about 9 liters of purified water and heat to a temperature of80° C.

[0118] Dissolve NIPAGIN and EDTA disodium.

[0119] Stir the solution constantly to complete dissolution of thecomponents.

[0120] Cool the obtained solution to room temperature.

[0121] Dissolve KETOROLAC® tromethamine and glycocholic acid bystirring.

[0122] Bring to volume with water.

EXAMPLE 15

[0123] Composition % For 10 Liters KETOROLAC ® tromethamine 15 1500 gEDTA disodium 0.01 1 g NIPAGIN 0.2 20 g Glycocholic acid 0.3 30 g LutrolF 127 15 1500 g Purified water, q.s. to 100 10 L

[0124] Method of Preparation

[0125] In a suitable vessel equipped with mixer and heating sleeve,introduce about 8 liters of purified water and heat to a temperature of80° C.

[0126] Dissolve NIPAGIN and EDTA disodium.

[0127] Stir the solution to 4° C. and then, maintaining it between 4°and 6° C. throughout the operation, gradually add Lutrol F127 withstirring.

[0128] Continue stirring to complete hydration of the polymer.

[0129] Bring the solution to room temperature.

[0130] Dissolve KETOROLAC® tromethamine and glycocholic acid.

[0131] Bring to volume with water. APPENDIX OF PRODUCT NAMES ANDEXAMPLES OF COMMERCIAL SOURCES KETOROLAC TROMETHAMINE: SYNTEX IRELAND,CLARECASTLE, IRELAND HYDROXYPROPYLCELLULOSE (KLUCEL) DOW CHEMICAL CO,MIDLAND MI USA HYDROXYPROPYLMETHYLCELLULOSE (METHOCEL) DOW CHEM. CO,MIDLAND MI HYDROXYETHYLCELLULOSE (NATROSOL) HERCULES INC, WILMINGTON DEUSA SODIUM CARBOXYMETHYLCELLULOSE (BLANOSE) HERCULES INC, WILMINGTON DECARBOPOL:BF GOODRICH CHEMICAL CO., CLEVELAND, OH, USA POLYCARBOPHIL: BFGOODRICH CHEMICAL CO., CLEVELAND, OH, USA GUM TRAGACANTH: COLONY IP. &EXP. CO., NEW YORK, NY, USA GUM XANTHAN: ALDRICH CHEMIE, STANHEIM,GERMANY SODIUM ALGINATE: EDWARD MANDELL CO., CARMEL, NEW YORK, USA AGARAGAR: ALDRICH CHEMIE, STANHEIM, GERMANY POLOXAMER (LUTROL f127): BASFWYNDOTTE CORP., PARSIPPANY, NJ, USA ETHYL ALCOHOL: EASTMAN CHEMICALPRODUCTS INC., KINOSPORT, TN, USA ISOPROPYL ALCOHOL: BAKER CHEMICAL CO.,NEW YORK, NY, USA PROPYLENE GLYCOL: DOW CHEMICAL CO., MIDLAND, MI, USAPOLYETHYLENE GLYCOL: BASF WYNDOTTE CORP., PARSIPPANY, NJ, USADIISOPROPYLADIPATE: CRODA, GOOLE, NORTH HUMERSIDE, UK SODIUMGLYCOCHOLATE: SIGMA CHEMICAL COMPANY, ST. LOUIS, MO, USALYSOPHOSPHATIDYLCHOLINE: AMERICAN LECITHIN, LONG ISLAND, NY, USAMETHYLPARAOXYBENZOATE (NIPAGIN): BDH CHEMICAL LTD, POOLE, DORSET, UKPROPYLPARAOXYBENZOATE: BDH CHEMICAL LTD, POOLE, DORSET, UK SODIUMBENZOATE: PFIZER INC., NEW YORK, NY, USA. BENZYL ALCOHOL: BDH CHEMICALLTD, POOLE DORSET, UK BENZALCONIUM CHLORIDE: ION PHARMACEUTICALS,COVINA, CA, USA CHLORBUTANOL: EASTERN CHEMICAL PRODUCTS, SMITHTOWN, NYUSA EDTA DISODIUM: GRACE AND CO., LONDON, UK. POE (9) LAURYL ALCOHOL:BASF WYNDOTTE CORP, PARSIPPANY, NJ, USA TROMETHAMINE: FARMITALIA, MILAN,ITALY GLYCEROL: DOW CHEMICAL CO., MIDLAND, MI, USA SODIUM CHLORIDE:ALDRICH CHEMIE, STANHEIM, GERMANY GLUCOSE: ROQUETTE LTD, TUNBRIDGEWELLS, KENT, UK

What is claimed is:
 1. An analgesic/anti-inflammatory pharmaceuticaldosage form which comprises an effective amount of an active ingredientselected from the group consisting of racemic5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, of the formula

optically active forms thereof and pharmaceutically acceptable saltsthereof, in combination with a pharmaceutically acceptable excipient ordiluent, said dosage form being an intranasally administrable dosageform.
 2. The dosage form of claim 1 comprising 0.5-40 mg of said activeingredient.
 3. The dosage form of claim 2 comprising 2-20 mg of saidactive ingredient.
 4. The dosage form of claim 1 comprising 5-20% ofsaid active ingredient (weight/volume).
 5. The dosage form of claim 1 ina single-dose form.
 6. The dosage form of claim 1 in the form of asolution or suspension.
 7. The dosage form of claim 1 containing 15% ofsaid active ingredient.
 8. The dosage form of claim 1 wherein saidexcipient comprises a bioadhesive.
 9. The dosage form of claim 1 whereinsaid excipient comprises a polymer that dissolves vehicle viscositybased on temperature change, to increase said viscosity at bodytemperature.
 10. The dosage form of claim 1 further comprising as anexcipient an intranasal absorption promoter.
 11. The dosage form ofclaim 10 wherein said promoter is selected from the group consisting ofPOE (9) lauryl alcohol and sodium glycocholate and lysophosphatidylcholine.
 12. A method for the treatment of inflammatory processes andpain of a traumatic or pathologic origin, which comprises theadministration by the intranasal route of an effective amount of theactive ingredient 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylicacid, in a racemic or optically active form or in the form of apharmaceutically acceptable salt.
 13. A method according to claim 8wherein said effective amount is within the range of 0.5-40 mg.
 14. Amethod according to claim 8 wherein said effective amount is within therange of 5-30 mg.
 15. A method according to claim 8 wherein saideffective amount is within the range of 5-20% (weight/volume).
 16. Amethod according to claim 8 wherein said effective amount is within therange of 15% (weight/volume).
 17. A method for the treatment ofinflammatory processes and pain of a traumatic or pathologic originwhich comprises the administration by the intranasal route of a dosageform according to claim
 1. 18. A method according to claim 17 whereinsaid mammal is a human and wherein said effective amount is sufficientto generate a plasma concentration of5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid within the rangebetween 0.3 and 5 mg/liter of plasma.